Asthma is a major public health problem affecting 15 million people in the United States alone. IL-13 is a critical mediator of allergic airway disease in humans and in mouse models. Its diverse functions are mediated by a complex receptor system that includes IL-4R&#945;, IL-13R&#945;1, and IL-13R&#945;2. IL-4R&#945;and IL- 13R&#945;1 form a high affinity signaling heterodimer that specifically binds IL-13 and signals. In contrast, IL- 13R&#945;2 has a short cytoplasmic tail that lacks known signaling motifs suggesting that it has no direct signaling ability. The inability of IL-13R&#945;2 expression to confer IL-13 responsiveness despite high affinity binding, and the presence of significant quantities of soluble IL-13R&#945;2, even in na[unreadable]ve mice, suggests that IL- 13R&#945;2 is a decoy receptor. Indeed, characterization of IL-13R&#945;2-deficient mice has revealed that IL-13R&#945;2 can downregulate IL-13 responses by sequestering IL-13. Although IL-13R&#945;2 clearly plays a role in downregulating IL-13 reponses, there is evidence that IL-13R&#945;2 may also contribute to allergic responses. Recent studies have shown that IL-13 can signal through IL-13R&#945;2 to stimulate TGF&#946;-mediated fibrosis. Furthermore, our own studies demonstrate that IL-13R&#945;2 can both promote and inhibit the development of airway hyperresponsiveness (AHR) and allergic inflammation. In mice, there are distinct membrane and soluble forms of IL-13R&#945;2. In contrast, recent data from our lab and others support that humans lack soluble IL-13R&#945;2 highlighting the potential importance of membrane IL-13R&#945;2 in humans. Our data support that membrane IL-13R&#945;2 can contribute to allergic airways hyperresponsiveness in vivo. We hypothesize that membrane and soluble IL-13R&#945;2 have distinct roles in regulating IL-13 responses, including the development of airway hyperresponsiveness and allergic inflammation. In order to address this hypothesis, we have generated a humanized mouse model in which IL-13R&#945;2 is expressed only in mouse lungs and only in the membrane form. We will use these mice, as well as mice that we have generated that exclusively express soluble IL-13R&#945;2 in their lungs. We will also utilize primary and cultured human cells to define the role of membrane IL-13R&#945;2. The IL-13 pathway is an attractive target for therapeutic intervention in allergic disorders. Conclusions derived from data generated in mouse systems are likely not relevant to human biology since humans lack appreciable soluble serum IL-13R&#945;2. It is critical to delineate the roles of membrane versus soluble IL-13R&#945;2 to enable the design of the most effective targeted therapies.